Intravenous Lidoflazine in Healthy Volunteers

Summary

Lidoflazine, an antianginal agent with some calcium antagonistic properties, has been advocated to protect tissues against ischaemic damage. Previous studies of the pharmacokinetics of lidoflazine have only concerned oral administration. Lidoflazine 0.5 and 1.0 mg/kg bodyweight was given intravenously (10-minute infusion) to 7 healthy volunteers (an eighth subject received the low dose only). Blood samples were drawn at frequent intervals, and urine was collected at intervals.

Peak plasma concentrations measured by gas chromatography ranged from 79 to 176 µg/L after 0.5 mg/kg and from 129 to 1400 µg/L after 1.0 mg/kg. The plasma concentration-time curves showed a triexponential decay, with a mean half-time of the elimination phases α, β and γ of 3.4 minutes, 2.6 hours and 16.4 hours, respectively. The largest fraction of dose, about 75%, was eliminated during the third phase. At 5 to 8 hours a second peak appeared in some of the subjects, which could reflect enterohepatic circulation of the drug. The volume of distribution (V_ss) averaged 10.4 L/kg. Plasma clearance averaged 0.59 L/kg/h. Urinary recovery was less than 10% of unchanged drug.

In summary, lidoflazine is initially rapidly eliminated from the circulation, probably due to a combination of extensive tissue distribution and uptake by the liver (metabolism). After 4 to 6 hours the plasma concentration falls much more slowly possibly reflecting release from tissue binding (lidoflazine has a high lipid solubility) and, in some cases, possibly enterohepatic recirculation. The terminal elimination phase (γ) will influence the steady-state pharmacokinetics the most. Conditions affecting the organ distribution of blood flow, e.g. shock or physical exercise, could have an important influence on the pharmacokinetics of lidoflazine.